KCNQ2/3 channels and interneuron physiology

KCNQ2/3通道已成为新生儿大脑兴奋性的重要调节因子，其突出表现为 几种功能丧失和功能获得的KCNQ2和KCNQ3变体已被发现在慢性阻塞性肺疾病患者中 新生儿和婴儿癫痫性脑病。因此，更好地理解 大脑中的神经元KCNQ2/3通道对于开发新生儿癫痫的新疗法至关重要。 在过去的几年里，我们在确定KCNQ2和KCNQ2的不同作用方面取得了进展 KCNQ3通道在锥体神经元兴奋性调控和多膜调节中的作用 导电性。在这里，我们建议进行实验，以解决与该函数有关的重要悬而未决的问题 中间神经元KCNQ2/3钾通道的特性。中间神经元对形成 神经元群的活动和促进兴奋性突触回路的发展。KCNQ2/3 当中间神经元尚未完全发育其分支时，通道在发育早期表达 独特的钾通道，增加了KCNQ2/3通道控制神经元间特性的可能性 处于早期发育阶段。一种解释是神经元间兴奋性的降低会导致 癫痫脑病中功能获得KCNQ2/3变异的过度兴奋性表型。因此， 阐明KCNQ2/3通道在神经元间兴奋性中的作用，并探索已知的功能获得KCNQ2/3变体的影响，将为健康和疾病中的皮质生理学提供新的见解。为此， 我们将：(I)确定KCNQ2/3通道在未成熟小白蛋白(PV)中的功能-以及 生长抑素(SST)阳性中间神经元的细胞类型特异性遗传学，(Ii)确定 来自中间神经元的KCNQ2/3消融导致体内外网络兴奋性，以及(Iii)确定 功能增益KCNQ2/3变异是否导致神经元间兴奋性低下 兴奋性网络过度兴奋性。拟议的研究将对我们更广泛的 了解KCNQ2/3通道如何控制神经元兴奋性，为预防奠定基础 以及治疗神经疾病，如儿童癫痫。

KCNQ2/3 channels have emerged as essential regulators of neonatal brain excitability, highlighted by the several loss- and gain-of-function KCNQ2 and KCNQ3 variants that have been identified in patients with neonatal and infantile epileptic encephalopathy. Therefore, an improved understanding of the function of neuronal KCNQ2/3 channels in the brain is paramount for developing new therapeutics for neonatal epilepsy. Over the last several years, we have made progress in determining the differential roles of KCNQ2 and KCNQ3 channels in controlling pyramidal neuron excitability and in mediating multiple membrane conductances. Here we propose experiments to tackle important outstanding questions regarding the function and properties of KCNQ2/3 potassium channels in interneurons. Interneurons are critical for shaping the activity of neuronal populations and promoting the development of excitatory synaptic circuits. KCNQ2/3 channels are expressed early in development when interneurons have not yet fully developed their clade of unique potassium channels, raising the possibility that KCNQ2/3 channels might control interneuron properties at early developmental stages. One explanation is that a decrease in interneuron excitability leads to the hyperexcitability phenotype of the gain-of-function KCNQ2/3 variants in epileptic encephalopathy. Thus, elucidating the role of KCNQ2/3 channels in interneuron excitability and exploring the effects of known gain-of-function KCNQ2/3 variants will shed new insights into cortical physiology in health and disease. To this end, we will: (i) determine the function of KCNQ2/3 channels in immature parvalbumin (PV)- and somatostatin (SST)-positive interneurons using cell-type specific genetics, (ii) determine whether Kcnq2/3 ablation from interneurons leads to network excitability ex vivo and in vivo, and (iii) determine whether gain-of-function KCNQ2/3 variants lead to interneuron hypoexcitability and subsequent excitatory network hyperexcitability. The proposed research will significantly contribute to our broader understanding of how KCNQ2/3 channels control neuronal excitability, building a foundation for the prevention and treatment of neurological disorders such as pediatric epilepsy.